A B cell receptor (BCR) is composed of membrane immunoglobulin (mIg) molecules assembled with heterodimers of Igα (CD79A) and Igβ (CD79B). An antigen is bound to the mIg and allow the receptors to aggregate, and an Igα/Igβ subunit transmits a signal to the inside of a B cell (Mol. Immunol., Vol. 41, p. 599-613, 2004).
As for a protein family of an Fcγ receptor (FcγR) which is an Fc receptor against an IgG antibody, FcγRIa (CD64A), FcγRIIa (CD32A), and FcγRIIIa (CD16A) which have immunoactive functions, and FcγRIIb (CD32B) which has immunosuppressive functions have been reported. It has been reported that when BCR and FcγRIIb on B cells are crosslinked through an IgG immune complex, an activity of the B cells is suppressed and thus a proliferation of the B cells and antibody production are suppressed (Nat. Rev. Immunol., Vol. 10, p. 328-343, 2010; Nat. Rev. Immunol., Vol. 8, p. 34-47, 2008; Nat. Rev. Immunol., Vol. 2, p. 580-592, 2002).
It has been reported that control of the activity of B cells through such FcγRIIb is deeply involved in the pathology of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
As for the relation to rheumatoid arthritis, it has been reported that in an FcγRIIb knockout mouse, humoral immunity is not appropriately controlled (Nature, Vol. 379, p. 346-349, 1996; J. Immunol., Vol. 163, p. 618-622, 1999) and susceptibility to collagen-induced arthritis is increased (J. Exp. Med., Vol. 189, p. 187-194, 1999). Further, it has been confirmed that expression of FcγRIIb in memory B cells of rheumatoid arthritis patients is decreased (J. Immunol., Vol. 190, p. 6015-6022, 2013).
As for the relation to systemic lupus erythematosus, it has been reported that onset of a systemic lupus erythematosus disease is significantly suppressed in a transgenic mouse in which expression of FcγRIIb is enhanced specifically in B cells (J. Exp. Med., Vol. 205, p. 883-895, 2008). It has been confirmed that in regard to a knockout mouse of FcγRIIb, self-reactive B cells or plasma cells appear and the disease condition of systemic lupus erythematosus develops spontaneously (Immunity, Vol. 13, p. 277-285, 2000; J. Exp. Med., Vol. 207, p. 2767-2778, 2010). Further, a decrease in expression of FcγRIIb in memory B cells of systemic lupus erythematosus patients (J. Exp. Med., Vol. 203, p. 2157-2164, 2006; J. Immunol., Vol. 178, p. 3272-3280, 2007) and relevance between genetic polymorphism in a cell transmembrane region of FcγRIIb and frequency of onsets of systemic lupus erythematosus (Arthritis Rheum., Vol. 46, p. 1242-1254, 2002) have been reported.
Further, suppression of antibody production by controlling an activity of B cells through FcγRIIb is effective for treating an autoimmune disease in which an autoantibody is related to the pathological condition.
Idiopathic thrombocytopenic purpura is an autoimmune disease in which an autoantibody against platelets of a patient causes platelet destruction (Autoimmun. Rev., Vol. 13, p. 577-583, 2014). It has been reported that in an animal to which an antiplatelet antibody is administered, thrombopenia is induced (Br. J. Haematol., Vol. 167, p. 110-120, 2014) and a decrease in an autoantibody are effective for the treatment of idiopathic thrombocytopenic purpura (Ther. Apher. Dial. Vol. 16, p. 311-320, 2012; Lupus, Vol. 22, p. 664-674, 2013).
Therefore, if a monoclonal antibody that crosslinks BCR and FcγRIIb and increases an immunosuppressive function of FcγRIIb can be developed, it is expected that such monoclonal antibody is useful for prevention or treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and idiopathic thrombocytopenic purpura.
As an antibody that crosslinks BCR and FcγRIIb, DART which is a bispecific antibody against Igβ and FcγRIIb (Patent Document 1 and Non-Patent Document 1), and anti-CD19 S267E/L328F which has a variable region binding to CD19 which is a part of a BCR complex and an Fc region whose affinity for FcγRIIb is increased (Patent Document 2 and Non-Patent Documents 2 and 3) are reported. Among these, anti-CD19 S267E/L328F is specifically examined, and its inhibitory action with respect to the activity of B cells in which BCR is stimulated and its lowering action of human blood antibody titer concentration in a mouse to which human peripheral blood mononuclear cells (PBMC) are transplanted are confirmed (Patent Document 2 and Non-Patent Documents 2 and 3).